CN103788083A - Method for preparing herbicide topramezone - Google Patents
Method for preparing herbicide topramezone Download PDFInfo
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- CN103788083A CN103788083A CN201410083163.0A CN201410083163A CN103788083A CN 103788083 A CN103788083 A CN 103788083A CN 201410083163 A CN201410083163 A CN 201410083163A CN 103788083 A CN103788083 A CN 103788083A
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- QUZPKSNSNPDALW-UHFFFAOYSA-N Bc(c(C)c1C2=NOCC2)ccc1SC Chemical compound Bc(c(C)c1C2=NOCC2)ccc1SC QUZPKSNSNPDALW-UHFFFAOYSA-N 0.000 description 1
- YTVRQRVLQGCTCE-JLHYYAGUSA-N CC/C(/c1c(C)cccc1N)=N\OC Chemical compound CC/C(/c1c(C)cccc1N)=N\OC YTVRQRVLQGCTCE-JLHYYAGUSA-N 0.000 description 1
- RLHWLUIUMHFALO-UHFFFAOYSA-N Cc(c(C1=NOCC1)c(cc1)S(C)=O)c1C(O)=O Chemical compound Cc(c(C1=NOCC1)c(cc1)S(C)=O)c1C(O)=O RLHWLUIUMHFALO-UHFFFAOYSA-N 0.000 description 1
- VOKYRHHSURLPLE-WEVVVXLNSA-N Cc1c(/C=N/O)c([N+]([O-])=O)ccc1 Chemical compound Cc1c(/C=N/O)c([N+]([O-])=O)ccc1 VOKYRHHSURLPLE-WEVVVXLNSA-N 0.000 description 1
- FVHAWXWFPBPFOS-UHFFFAOYSA-N Cc1c(C)c([N+]([O-])=O)ccc1 Chemical compound Cc1c(C)c([N+]([O-])=O)ccc1 FVHAWXWFPBPFOS-UHFFFAOYSA-N 0.000 description 1
- ZTJWBDREQSNUKG-UHFFFAOYSA-N Cc1c(C2=NOCC2)c(SC)ccc1 Chemical compound Cc1c(C2=NOCC2)c(SC)ccc1 ZTJWBDREQSNUKG-UHFFFAOYSA-N 0.000 description 1
- MTMYTPSSQJWYHK-UHFFFAOYSA-N Cc1c(C2=NOCC2)c(SC)ccc1C(O)=O Chemical compound Cc1c(C2=NOCC2)c(SC)ccc1C(O)=O MTMYTPSSQJWYHK-UHFFFAOYSA-N 0.000 description 1
- HYEDIIKBTFDHAR-UHFFFAOYSA-N Cc1c(C2=NOCC2)c([N+]([O-])=O)ccc1 Chemical compound Cc1c(C2=NOCC2)c([N+]([O-])=O)ccc1 HYEDIIKBTFDHAR-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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Abstract
The invention aims to provide a method for synthesis and preparation of [2-methyl-3- (4,5-dihydro-3-isoxazole)-4-(methyl sulfonyl) phenyl]-(5-hydroxy-1-methyl-1H-parazole-4-based) ketone (topramezone). According to the method, raw materials are simple and easy to obtain, post-processing is simple, the total recovery is high, the defects existing in the prior art and the defects concerning cost are overcome, and an important reference can be provided for industrial production.
Description
Technical field
The present invention relates to a kind of method of preparing weedicide benzene azoles humulone take 3-nitro o-Xylol as raw material.
Technical background
[2-methyl-3-(4; 5-dihydro-3-isoxazolyl)-4-(methyl sulphonyl) phenyl]-(5-hydroxyl-1-methyl isophthalic acid H-is than azoles-4-yl) ketone (Topramezone) benzene azoles humulone (CAS210631-68-8; the general Topramezone by name of ISO), its chemical structure is as follows:
Benzene azoles humulone be BASF Aktiengesellschaft find and exploitation structure in comprise pyrazoles with p-hydroxybenzene pyruvate dual oxide enzyme (4-HPPD) inhibitor of two kinds of structures of isoxazole simultaneously, 4-HPPD inhibitor be the new weedicide target determined the nineties in 20th century it by suppressing the 4-medical midbodies of para (ortho)-hydroxybenzoic acetone acid dual oxide enzyme (HPPD) in plastoquinone biosynthesizing, thereby remote effect carotenoid is synthetic, disturb chloroplast(id) synthetic and function under illumination, finally cause weeds death.Due to the mechanism of action difference of HPPD inhibitor in animal and plant body, so it is to being safe to Mammals.Therefore, up to now, the HPPD inhibitor class weedicide of having developed is still one of weedicide kind to mammalian toxicity minimum at present, not yet finds the bibliographical information of its resistance aspect at present, and therefore, this is the good light-dependent type weedicide of a class development prospect.
Benzene azoles humulone can be used for cauline leaf processing after corn field seedling, is a kind of broad weed-killing spectrum, applied widely, safe, speed of action fast, the weedicide compatible good with other weedicides.Broad weed-killing spectrum shows that it is to corn field annual gramineae and broadleaf weeds, as to have good action with the annual grassy weeds such as lady's-grass, Herba Eleusines Indicae, Herba Setariae Viridis, bare headed barnyard grass, Mazus japonicus, Herba galinsogae parviflorae, recessed amaranth, cyperus iria, flat fringe nutgrass flatsedge, piemarker and spontaneous Brassica campestris L seedling, malignant weed is as Herba Acalyphae, Herba Commelinae, meal bud grass, Herba Oxalidis Corniculatae, Herba Murdanniae Triquetrae etc., can be mixed with atrazine 90% wettable powder 50g, can reach good herbicidal effect; The scope of using extensively shows that general after-seedling herbicide for maize can only be in the 2-6 of corn leaf phase medication, exceedes this medication in period and just has obvious poisoning, and benzene azoles humulone is wider duration of service; Benzene azoles humulone is except general corn in addition, and to sweet corn, Glutinous Semen Maydis and pop corn security are also very high, and therefore, benzene azoles humulone is to be considered in the market safest in domestic and international all after-seedling herbicide for maize kinds; Add the fast performance of its speed of action be used in medicine after 2～5 days effects remarkable; And compatible good, can mix use with atrazine, primisulfuronmethyl, nicosulfuron and metolachlor, obtain good herbicidal effect.So, within 2009, defend listing in China with trade(brand)name bud when benzene azoles humulone, its market response is positive, stand like the legs of a tripod with nicosulfuron, mesotrione, be widely applied rapidly at home, become the main product in corn field herbicide market, have good application prospect.
Find by detailed investigation of related literatures; because benzene azoles humulone is still in patent protection period; the domestic research about benzene azoles humulone at present mainly concentrates on its mechanism of action; the aspect such as separation and quantitative analysis of field application, safety research and former medicine; about synthetic document less, BASF Aktiengesellschaft and Tso Tat Co., Ltd., Japan and the respectively synthetic patent report that did to benzene azoles humulone.Wherein the initial feed 3-dimethyl-4-methyl sulfonylbenzoic acid methyl esters in the patent route of Cao Da company report is difficult to obtain, do not have on the market ready-made product to sell, and the step that has multistep not react completely in experiment, need to carry out column chromatography purification separation; In addition, this route is also used the poisonous reagents such as acetone cyanohydrin, and overall yield only has 5% left and right; Route is long, and overall yield is low, and cost is high, and troublesome poeration is unfavorable for suitability for industrialized production.BASF AG has reported two complete synthetic routes and several possible synthetic routes, and wherein two complete path overall yields of report can reach more than 20%, but multistep need to be used high pressure and heating installation, high to equipment requirements; Need in addition to use the noble metal such as palladium metal, metal platinum compound catalyst, these catalyzer are expensive, recovery difficulty, make total cost higher.
This paper provides a kind of method of synthetic benzene azoles humulone, has been intended to avoid be difficult in BASF synthetic method the use of expensive palladium metal/platinum class catalyzer of recycling, and concrete reaction scheme is as follows:
Take 3-nitro o-Xylol as starting raw material, through oximate, addition, reduction, diazotization, bromo, carry out the exchange of halogen lithium with n-Butyl Lithium after with carbon dioxide reaction, oxidation, with and the condensation of 1-methyl-5-hydroxypyrazoles reset eight steps and react and obtain final product benzene azoles humulone, under optimal conditions, overall yield 30.2%.Its raw material is simple and easy to get, and aftertreatment is simple, and total recovery is higher, can provide important reference for suitability for industrialized production.
Summary of the invention
The object of this invention is to provide one [2-methyl-3-(4; 5-dihydro-3-isoxazolyl)-4-(methyl sulphonyl) phenyl] method of synthetic preparation of-(5-hydroxyl-1-methyl isophthalic acid H-pyrazoles-4-yl) ketone (Topramezone); its raw material is simple and easy to get; aftertreatment is simple; total recovery is higher; to overcome the defect existing on prior art and cost, can provide important reference for suitability for industrialized production.
Method of the present invention, comprise the steps: take the compound shown in formula (IX) as starting raw material, through the compound shown in oximation reaction synthesis type (VIII), through the compound shown in addition reaction synthesis type (VII), through the compound shown in reduction synthesis type (VI), become the compound shown in formula V through diazo compounds, through the compound shown in bromo synthesis type (IV), after n-Butyl Lithium carries out the exchange of halogen lithium with the compound shown in carbon dioxide reaction synthesis type (III), then through the compound shown in peroxidation synthesis type (II), finally by crossing and the target product shown in 1-methyl-5-hydroxypyrazoles condensation rearrangement reaction synthesis type (I).
Reaction expression is as follows:
Compound (VIII) can adopt the method for reporting in patent US20026469176B1 to be prepared, and reaction expression is as follows:
Compound (VII) can adopt the method for reporting in patent US20026469176B1 to be prepared, and reaction expression is as follows:
Compound shown in formula (VI), can adopt the compound shown in formula (VII) is that starting material are prepared, preparation method comprises the steps:
Under specific temperature condition, compound 3-shown in formula (VII) (2-methyl-6-nitrophenyl)-4,5-dihydro-isoxazole and two hydrated stannous chlorides in ethanol, reacting by heating, temperature of reaction is 0～100 ℃, reaction times is 1～24h, underpressure distillation is except ethanol, and sodium hydroxide regulates pH to alkalescence, ethyl acetate extraction, then the compound shown in collection type (VI) from ethyl acetate solution, yield 91.3%.
The weightmeasurement ratio of the compound shown in formula (VII) and ethanol is 0.05～0.2g/ml, is preferably 0.1～0.15g/ml;
Compound shown in formula (VII): two hydrated stannous chloride=0.1～1: 1, be preferably 0.2～0.3: 1;
Reaction expression is as follows:
Compound (V) can adopt the method for reporting in patent US20026469176B1 to be prepared, and suitable temperature is 0～25 ℃, otherwise produces by product 3-o-tolyl-4 of deaminizating, 5-dihydro-isoxazole, and reaction expression is as follows:
Compound shown in formula (IV), can adopt the compound shown in formula (V) is that starting material are prepared, preparation method comprises the steps:
By the compound 3-shown in formula (V) (2-methyl-6-methylthio group phenyl)-4,5-dihydro-isoxazole and bromine are dissolved with chloroform, stir, temperature of reaction is-10～50 ℃, and preferably 0～25 ℃, the reaction times is 0.5～24 hour, after reaction finishes, reaction solution washs with saturated sodium bicarbonate and saturated nacl aqueous solution, the then compound shown in collection type (IV) from chloroformic solution, yield 84.3%.
The weightmeasurement ratio of the compound shown in formula (V) and chloroform is 0.03～0.15g/ml, preferably 0.05～0.1g/ml;
Compound shown in formula (V): bromine=0.1～1.0: 1, preferably 0.8～1.0: 1;
Reaction expression is as follows:
With the compound 3-shown in formula (IV) (the bromo-6-methylthio group of 2-methyl-3-phenyl)-4, 5-dihydro-isoxazole is starting raw material, compound shown in synthesis type (III), comprise the steps: 3-(the bromo-6-methylthio group of 2-methyl-3-phenyl)-4, 5-dihydro-isoxazole dissolves with tetrahydrofuran (THF), drip n-Butyl Lithium hexane solution, under low temperature, react, temperature of reaction is-100～0 ℃, preferably-100～-60 ℃, reaction times is 0.5～24 hour, after completion of the reaction, pour reaction solution into existing mill dry ice, add water, sodium hydroxide regulates reaction solution to alkalescence, ether washing, hydrochloric acid regulates water pH, solid is separated out, compound shown in collection type from reaction product (III), yield 84.4%.
Compound shown in formula (IV) and the weightmeasurement ratio of tetrahydrofuran (THF): 0.02～0.10g/ml;
Compound shown in formula (IV): n-Butyl Lithium=0.1～1.0: 1;
N-Butyl Lithium is that concentration is the hexane solution of 2.5mol/L;
Reaction expression is as follows:
By the compound shown in the compounds accepted way of doing sth (II) shown in formula (III), comprise the steps:
By compound (III) 2-methyl-3-(4,5-dihydro-isoxazole-3-yl)-4-methylthio-benzoic acid and certain density hydrogen peroxide be in Glacial acetic acid, heating, temperature of reaction is 0～150 ℃, and the reaction times is 0.5～24 hour, after completion of the reaction, pour frozen water into, ethyl acetate extraction, the then compound shown in collection type (II) from ethyl acetate solution, yield 98.1%.
Compound shown in formula (III) and the weightmeasurement ratio of Glacial acetic acid: 0.05～0.20g/ml;
Compound shown in formula (III): hydrogen peroxide=0.5～1g/ml;
The concentration of hydrogen peroxide is 3.0～30%;
Reaction expression is as follows:
By the compound shown in the compounds accepted way of doing sth (I) shown in formula (II), comprise the steps:
(1) compound (II), thionyl chloride, pyridine are dissolved by dry benzene, heating, the temperature of reaction is 0～100 ℃, reaction times is 0.5～24 hour, after completion of the reaction, remove solvent and excessive thionyl chloride under reduced pressure, resistates dissolves with anhydrous dioxane;
(2) in reaction solution, add 1-methyl-5-hydroxypyrazoles, triethylamine, the reaction times is 0.5～24 hour, after completion of the reaction, and by filtered through silica gel, concentrate eluant;
(3), in concentrated elutriant, add dry salt of wormwood, heating, the temperature of reaction is 0～100 ℃, reaction times is 0.5～24 hour, after completion of the reaction, removes solvent under reduced pressure, resistates water dissolution, remove by filter insolubles, salt acid for adjusting pH, ethyl acetate extraction, then collection type (I) target product from ethyl acetate solution, yield 81.4%.
Compound (II) is 0.03～0.1: 1 with the ratio of the bulking value of dry benzene;
Compound (II) is 0.5～2.0: 1 with the ratio of the bulking value of thionyl chloride;
Compound (II) is 50～200: 1 with the ratio of the bulking value of pyridine, preferably 100～200: 1;
Compound (II) is 0.03～0.1: 1 with the ratio of the bulking value of dioxane;
Compound (II): 1-methyl-5-hydroxypyrazoles=0.2～1.0: 1, preferably 0.8～1.0: 1;
Compound (II): triethylamine=0.2～1.0: 1;
Compound (II): salt of wormwood=0.5～1.0: 1;
Reaction expression is as follows:
Embodiment:
Embodiment 1
Synthesizing of compound (VIII)
In 500ml reaction flask, add the DMF of 120ml, be cooled to-40 ℃, slowly add 33.6g potassium methylate in batches, stir.Then under violent stirring, 30g (0.2mol) 3-nitro o-Xylol and 27.4g nitrous acid straight butyl mixed solution are slowly added drop-wise in reaction solution, temperature control-45～-35 ℃, use about 4.5h, dropwise and continue to react 3.5h at this temperature.After completion of the reaction, slowly drip 40mL water, then add 40mL Glacial acetic acid to regulate reaction solution pH to 5～6, below temperature control-5 ℃, then reaction solution is poured in 600ml frozen water, stir 30min, suction filtration, filter cake washing, dry, obtain 30.9g light gray-white solid.Thick product joins in 100ml toluene, and stirring at room temperature 1.5h filters, and obtains 29.8g rice white pulverulent solids product, yield 83.4% after filtration cakes torrefaction.
1H?NMR(CDCl
3，300Hz)δ：2.32(s，3H，CH
3)，7.52(t，1H，Ar-H)，7.65(d，1H，Ar-H)，7.84(s，1H，Ar-H)，11.33(s，1H，NOH)；ESI-MS：181.1[M+H]
+.
Embodiment 2
Synthesizing of compound (VII)
In 250ml reaction flask, add 10.8g (0.06mol) 2-methyl-6-nitrobenzoyl aldoxime, dissolve with 100ml acetonitrile, be heated to 60 ℃, add micro-N-chlorosuccinimide, question response starts, cooling a little reaction solution, after being dissolved with 60ml acetonitrile, 8.2gN-chlorosuccinimide is slowly added drop-wise in reaction solution in 40～50 ℃, drip and continue to stir 30min, remove acetonitrile under reduced pressure, resistates stirs 1h after dissolving with 150ml toluene, suction filtration, filtrate is transferred in 250ml autoclave, slowly drip 6.0g triethylamine, then pass into ethene and react 8h under 6bar pressure.After reaction finishes, reaction solution is used respectively saturated sodium bicarbonate solution and water washing, and anhydrous sodium sulfate drying removes solvent under reduced pressure, obtains 11.2g taupe lenticular product, yield 90.6%.
1H?NMR(CDCl
3，300Hz)δ：2.40(s，3H，CH
3)，3.32(t，2H,CH
2)，4.59(t，2H，CH
2)，7.48(t，1H，Ar-H)，7.56(d，1H,Ar-H)，7.97(d，1H,Ar-H)；ESI-MS：229.1[M+Na]
+.
Embodiment 3
Synthesizing of compound (VI)
In 250ml reaction flask, add 10.0g (0.05mol) 3-(2-methyl-6-nitrophenyl)-4,5-dihydro-isoxazole, 35g bis-hydrated stannous chlorides, use 150ml dissolve with ethanol, reflux 5h, be spin-dried for ethanol, resistates regulates pH to 10～11 with 20% sodium hydroxide, adds ethyl acetate, after fully stirring, suction filtration, filter cake washs by ethyl acetate, and filtrate water is washed three times, anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain 7.8g taupe lenticular product, yield 91.3%.
1H?NMR(CDCl
3，300Hz)δ：2.27(s，3H，CH
3)，3.26(t，2H，CH
2)，4.10(s，2H，NH
2)，4.46(t，2H，CH
2)，6.61(t，2H，Ar-H)，7.06(t，1H,Ar-H)；ESI-MS：199.1[M+Na]
+.
Embodiment 4
Synthesizing of compound (V)
In 250ml reaction flask, add successively 10g (0.057mol) 2-(4,5-dihydro-isoxazole-3-yl)-3-monomethylaniline, 75ml Methyl disulfide, 0.Sg copper powder, drips 6.5g nitrite tert-butyl under condition of ice bath, dropwise under room temperature and react 8h.Question response finishes, reclaim under reduced pressure Methyl disulfide, resistates acetic acid ethyl dissolution, use respectively 20% hydrochloric acid, saturated sodium bicarbonate solution and water washing, anhydrous sodium sulfate drying, removes solvent under reduced pressure, obtains 10.6g Vandyke brown oily liquids, after cooling placement, become Vandyke brown solid, yield 90.1%.
1H?NMR(CDCl
3，300Hz)2.29(s，3H，Ar-CH
3)，2.45(s，3H，SCH
3)，3.30(t，2H，CH
2)，4.53(t，2H，CH
2)，7.07(q，1H，Ar-H)，7.17(d，1H，Ar-H)，7.27(t，IH,Ar-H)；ESI-MS：230.1[M+Na]
+
Embodiment 5
Synthesizing of compound (IV)
In 250ml reaction flask, add 6.2g (0.03mol) 3-(2-methyl-6-methylthio group phenyl)-4,5-dihydro-isoxazole, with the dissolving of 100ml chloroform, after 4.8g bromine is dissolved with 20ml chloroform, under condition of ice bath, be slowly added drop-wise in reaction flask, use about 1h.Then in 20～25 ℃ of reaction 6h.After question response finishes, reaction solution is used respectively to saturated sodium bicarbonate solution and saturated common salt water washing, anhydrous sodium sulfate drying, removes solvent under reduced pressure, obtains 6.2g yellowish brown oily solid, yield 72.1%.
1H?NMR(CDCl
3，300Hz)δ：2.35(s，3H，Ar-CH
3)，2.45(s，3H，SCH
3)，3.27(t，2H，CH
2)，4.56(t，2H，CH
2)，7.03(d，1H,Ar-H)7.56(d，1H，Ar-H)；ESI-MS：308.0，310.0[M+Na]
+
Embodiment 6
Synthesizing of compound (III)
In 250ml reaction flask, add 7.4g (0.026mol) 3-(the bromo-6-methylthio group of 2-methyl-3-phenyl)-4, 5-dihydro-isoxazole, dissolve with 100ml tetrahydrofuran (THF), under nitrogen protection, slowly drip 2.5M n-Butyl Lithium hexane solution 12.5ml in-78 ℃, add rear continuation and stir 1h, then reaction solution is poured in existing mill dry ice, slowly rise to room temperature, add water, by extremely alkalescence of 10% sodium hydroxide adjusting reaction solution, water washs with ether, then regulate water pH to 2～3 with 20% hydrochloric acid, a large amount of solids are separated out, suction filtration, dry, obtain pale powder solid 5.5g, yield 84.4%.
1H?NMR(DMSO，300Hz)δ：2.38(s，3H，Ar-CH
3)，2.49(s，3H，SCH
3)，3.23(t，2H，CH
2)，4.44(t，2H，CH
2)7.27(d，1H，Ar-H)，7.85(d，1H，Ar-H)，12.85(br，1H，COOH)；ESI-MS：250.0[M-H]
-.
Embodiment 7
Synthesizing of compound (II)
In 250ml reaction flask, add 9.5g (0.038mol) 2-methyl-3-(4,5-dihydro-isoxazole-3-yl)-4-methylthio-benzoic acid, 100ml Glacial acetic acid, be heated to 60 ℃, slowly drip the hydrogen peroxide that 13g massfraction is 30%, temperature control 60-65 ℃, drips rear continuation reaction 4h.Question response finishes, and cooling reaction solution is poured in frozen water, stirs 30min, is extracted with ethyl acetate, and organic layer washes with water, and anhydrous sodium sulfate drying removes solvent under reduced pressure, obtains 10.5g pale solid product, yield 98.1%.
1H?NMR(DMSO，300Hz)δ：2.42(s，3H，Ar-CH
3)，3.24(s，3H，SO
2CH
3)，3.33(t，2H，CH
2)，4.47(t，2H，CH
2)，7.99(m，2H，Ar-H)13.60(br，1H，COOH)；ESI-MS：282.1[M-H]
-
Embodiment 8
Synthesizing of compound (I)
In 100ml reaction flask, add 4.5g (0.016mol) 2-methyl-3-(4,5-dihydro-isoxazole-3-yl)-4-methyl sulfonylbenzoic acid, with the dissolving of 50ml dry benzene, then add 2.8ml thionyl chloride and 1 pyridine, reflux 3h.Cooling reaction solution, remove solvent and excessive thionyl chloride under reduced pressure, the resistates obtaining dissolves with the anhydrous dioxane of 30ml, is added drop-wise in the anhydrous dioxane solution of 30ml of 1.75g (0.018mol) 1-methyl-5-hydroxypyrazoles, drip again 1.9g triethylamine, under room temperature, stir 3h.After reaction solution is concentrated, with filtered through silica gel (elutriant is dioxane), the elutriant obtaining is concentrated into 50ml, adds the salt of wormwood of 1.85g drying and grinding, reflux 6h.Question response finishes, and removes solvent under reduced pressure, and resistates water dissolution, removes by filter insolubles, filtrate regulates pH to 2-3 with 10% dilute hydrochloric acid, ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying, removes solvent under reduced pressure and obtains 4.7g white crystal compound, yield 81.4%.
1H?NMR(CDCl
3，300Hz)δ：2.38(s，3H，Ar-CH
3)，3.32(s，3H，SO
2CH
3)，3.32(bs，2H，CH
2)，3.74(s，3H，Py-CH
3)，4.61(t，2H，CH
2)，6.14(br，1H，OH)，7.36(s，1H，Py-H)7.67(d，1H，Ar-H)，8.11(d，1H，Ar-H)；ESI-MS：362.2[M-H]
-。
Claims (12)
1.[3-(4, 5-dihydro-3-isoxazolyl)-2-methyl-4-(methyl sulphonyl) phenyl] preparation method of-(5-hydroxyl-1-methyl isophthalic acid H-azoles-4-yl) ketone, it is characterized in that, comprise the steps: take the compound shown in formula (IX) as starting raw material, through compound shown in oximate synthesis type (VIII), process and compound shown in Addition on ethylene synthesis type (VII), through the compound shown in reduction synthesis type (VI), become the compound shown in formula V through diazo compounds, through the compound shown in bromo synthesis type (IV), compound (IV) carries out halogen lithium with n-Butyl Lithium and exchanges the compound shown in rear and carbon dioxide reaction synthesis type (III), then through the compound shown in peroxidation synthesis type (II), last 1-methyl-5-hydroxypyrazoles condensation is reset and is obtained benzene azoles humulone, reaction expression is as follows:
Wherein compound (VIII) can adopt the method for reporting in patent US20026469176B1 to be prepared, and reaction expression is as follows:
Wherein compound (VII) can adopt the method for reporting in patent US20026469176B1 to be prepared, and reaction expression is as follows:
2. method according to claim 1, it is characterized in that, by the compound shown in the compounds accepted way of doing sth (VI) shown in formula (VII), comprise the steps: under specific temperature condition, compound 3-shown in formula (VII) (2-methyl-6-nitrophenyl)-4,5-dihydro-isoxazole and two hydrated stannous chlorides are in ethanol, after reacting by heating, underpressure distillation is except ethanol, sodium hydroxide regulates pH to alkalescence, ethyl acetate extraction, the then compound shown in collection type (VI) from ethyl acetate solution.
3. method according to claim 2, is characterized in that: described temperature of reaction is 0～100 ℃, and the reaction times is 1～24h, and the weight ratio of each component is:
The weightmeasurement ratio of the compound shown in formula (VII) and ethanol is 0.05～0.2g/ml;
Compound shown in formula (VII): two hydrated stannous chloride=0.1～1: 1;
Reaction expression is as follows:
4. method according to claim 1, it is characterized in that: compound (V) can adopt the method for reporting in patent US20026469176B1 to be prepared, wherein suitable temperature is 0～25 ℃, and avoid the reacting by heating in document, otherwise produce by product 3-o-tolyl-4 of deaminizating, 5-dihydro-isoxazole, reaction expression is as follows:
5. method according to claim 1, it is characterized in that: by the compound shown in the compounds accepted way of doing sth (IV) shown in formula (V), comprise the steps: the compound 3-shown in formula (V) (2-methyl-6-methylthio group phenyl)-4,5-dihydro-isoxazole and bromine are dissolved with chloroform, under a certain temperature condition, stirring reaction 0～24h, reaction solution washs with saturated sodium bicarbonate and saturated nacl aqueous solution, then the compound shown in collection type (IV) from chloroformic solution.
6. method according to claim 5, is characterized in that: described temperature of reaction is-10～50 ℃, and the reaction times is 0.5～24 hour, and the weight ratio of each component is:
The weightmeasurement ratio of the compound shown in formula (V) and chloroform is 0.03～0.15g/ml;
Compound shown in formula (V): bromine=0.1～1.0: 1;
Reaction expression is as follows:
7. method according to claim 1, it is characterized in that: by the compound shown in the compounds accepted way of doing sth (III) shown in formula (IV), compound name shown in its Chinese style (IV) is called 3-(the bromo-6-methylthio group of 2-methyl-3-phenyl)-4, 5-dihydro-isoxazole, comprise the steps: 3-(the bromo-6-methylthio group of 2-methyl-3-phenyl)-4, 5-dihydro-isoxazole dissolves with tetrahydrofuran (THF), drip n-Butyl Lithium hexane solution, under low temperature after completion of the reaction, pour reaction solution into existing mill dry ice, add water, sodium hydroxide regulates reaction solution to alkalescence, ether washing, hydrochloric acid regulates water pH, solid is separated out, compound shown in collection type from reaction product (III).
8. method according to claim 7, is characterized in that: described temperature of reaction is-100～0 ℃, and the reaction times is 0.5～24 hour, and the weight ratio of each component is:
Compound shown in formula (IV) and the weightmeasurement ratio of tetrahydrofuran (THF): 0.02～0.10g/ml;
Compound shown in formula (IV): n-Butyl Lithium=0.1～1.0: 1;
N-Butyl Lithium is that concentration is the hexane solution of 2.5mol/L;
Reaction expression is as follows:
9. method according to claim 1, it is characterized in that: by the compound shown in the compounds accepted way of doing sth (II) shown in formula (III), comprise the steps: compound (III) 2-methyl-3-(4,5-dihydro-isoxazole-3-yl)-4-methylthio-benzoic acid and certain density hydrogen peroxide be in Glacial acetic acid, after reacting by heating, pour frozen water into, ethyl acetate extraction,, the then compound shown in collection type (II) from ethyl acetate solution.
10. method according to claim 9, is characterized in that: described temperature of reaction is 0～100 ℃, and the reaction times is 0.5～24 hour, and the weight ratio of each component is:
Compound shown in formula (III) and the weightmeasurement ratio of Glacial acetic acid: 0.05～0.20g/ml;
Compound shown in formula (III): hydrogen peroxide=0.5～1g/ml;
The concentration of hydrogen peroxide is 3.0～30%;
Reaction expression is as follows:
11. methods according to claim 1, is characterized in that: by the compound shown in the compounds accepted way of doing sth (I) shown in formula (II), comprise the steps:
(1) compound (II), thionyl chloride, pyridine are dissolved by dry benzene, reacting by heating is complete, removes solvent and excessive thionyl chloride under reduced pressure, and resistates dissolves with anhydrous dioxane;
(2) in reaction solution, add 1-methyl-5-hydroxypyrazoles, triethylamine, after completion of the reaction, filtered through silica gel, concentrate eluant;
(3) add dry salt of wormwood, after reacting by heating, remove solvent under reduced pressure, resistates water dissolution, removes by filter insolubles, salt acid for adjusting pH, ethyl acetate extraction, then collection type (I) target product from ethyl acetate solution.
12. methods according to claim 11, is characterized in that:
(1) in, the temperature of reaction is 0～100 ℃, and the reaction times is 0.5～24 hour; The weight ratio of each component is:
Compound (II) is 0.03～0.1: 1 with the ratio of the bulking value of dry benzene;
Compound (II) is 0.5～2.0: 1 with the ratio of the bulking value of thionyl chloride;
Compound (II) is 50～200: 1 with the ratio of the bulking value of pyridine;
Compound (II) is 0.03～0.1: 1 with the ratio of the bulking value of dioxane;
(2) reaction times is 0.5～24 hour; The weight ratio of each component is:
Compound (II): 1-methyl-5-hydroxypyrazoles=0.2～1.0: 1;
Compound (II): triethylamine=0.2～1.0: 1;
(3) in, the temperature of reaction is 0～100 ℃, and the reaction times is 0.5～24 hour; The weight ratio of each component is:
Compound (II): salt of wormwood=0.5～1.0: 1;
Reaction expression is as follows:
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